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Amyloid Beta induces oxidative stress-mediated blood-brain barrier changes in capillary amyloid angiopathy
Abstract
Cerebral amyloid angiopathy (CAA) is frequently observed in Alzheimer's disease (AD) and is characterized by deposition of amyloid beta (Aβ) in leptomeningeal and cortical brain vasculature. In 40% of AD cases, Aβ mainly accumulates in cortical capillaries, a phenomenon referred to as capillary CAA (capCAA). The aim of this study was to investigate blood-brain barrier (BBB) alterations in CAA-affected capillaries with the emphasis on tight junction (TJ) changes. First, capCAA brain tissue was analyzed for the distribution of TJs. Here, we show for the first time a dramatic loss of occludin, claudin-5, and ZO-1 in Aβ-laden capillaries surrounded by NADPH oxidase-2 (NOX-2)-positive activated microglia. Importantly, we observed abundant vascular expression of the Aβ transporter receptor for advanced glycation endproducts (RAGE). To unravel the underlying mechanism, a human brain endothelial cell line was stimulated with Aβ1-42 to analyze the effects of Aβ. We observed a dose-dependent cytotoxicity and increased ROS generation, which interestingly was reversed by administration of exogenous antioxidants, NOX-2 inhibitors, and by blocking RAGE. Taken together, our data evidently show that Aβ is toxic to brain endothelial cells via binding to RAGE and induction of ROS production, which ultimately leads to disruption of TJs and loss of BBB integrity.
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“Through these additional substrates, BACE1 has been implicated in inflammation, cardiovascular function, glucose homeostasis, and insulin signaling”
From BACE1: More than just a β‐secretase (2022) · cites this paper as [36]
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“Additionally, human CAA post-mortem capillaries with amyloid-β load are surrounded by NOX2-positive microglia [122,123].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [122]
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Metadata
- Authors
- Carrano, A., Hoozemans, J. J. M., van der Vies, S. M., Rozemuller, A. J. M., van Horssen, J., & de Vries, H. E.
- Affiliations
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Departments of Molecular Cell Biology and Immunology (MCBI) and Pathology, VU University Medical Center, Amsterdam, The Netherlands.
- Venue
- Antioxidants & Redox Signaling
- Publisher
- SAGE Publications
- Published
- 2011-09
- Volume
- 15
- Issue
- 5
- Pages
- 1167-1178
- ISSN
- 1523-0864 (ISSN-L)
- 1557-7716
- OpenAlex
- W2054446458
- Cited by
- 293
- References
- 50
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 30 · 2023: 21 · 2022: 34 · 2021: 27 · 2020: 21 · 2019: 13 · 2018: 17 · 2017: 11 · 2016: 18 · 2015: 20 · 2014: 14 · 2013: 16 · 2012: 10
- FWCI
- 9.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Antioxidants and Redox Signaling (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- VU Research Portal (publishedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Chinese Academy of Agricultural Sciences
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Keywords
- cerebral amyloid angiopathy, amyloid-beta, blood-brain barrier, tight junctions, oxidative stress, reactive oxygen species, NADPH oxidase 2, microglia, receptor for advanced glycation end products, RAGE, brain endothelial cells, occludin, claudin-5, ZO-1, Alzheimer's disease, antioxidant defense
- MeSH terms
- Receptor for Advanced Glycation End Products, NADPH Oxidase 2, Aged, Aged, 80 and over, Antioxidants, Blood-Brain Barrier, Capillaries, Cell Line, Female, Gene Expression Regulation, Humans, Male, Membrane Glycoproteins, Membrane Proteins, Phosphoproteins, RNA, Messenger, Down-Regulation, Amyloid beta-Peptides, Cerebral Amyloid Angiopathy, Reactive Oxygen Species, Microglia, Oxidative Stress, Tight Junctions, NADPH Oxidases, Endothelial Cells, Occludin, Zonula Occludens-1 Protein
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